Methanesulphonamido-benzofuran, preparation method and use thereof as synthesis intermediate

ABSTRACT

The invention relates to 2-butyl-5-(methanesulfonamido)benzofuran, its preparation and its use.  
     This compound is a synthesis intermediate, in particular for the preparation of dronedarone.

[0001] The present invention relates, in a general. way, to a(methanesulfonamido)benzofuran derivative, to its method of preparationand to its use as a synthesis intermediate.

[0002] More precisely, the subject of the invention is2-butyl-5-(methanesulfonamido)benzofuran of formula:

[0003] This compound has proved particularly useful as an intermediateproduct for the final preparation of (aminoalkoxybenzoyl)benzofuranderivatives, in particular of2-butyl-3-(4-[3-(dibutylamino)propoxy]-benzoyl)-5-(methanesulfonamido)benzofurancommonly called dronedarone and its pharmaceutically acceptable salts.

[0004] This (methanesulfonamido)benzofuran derivative and itspharmaceutically acceptable salts have been described in patentEP0471609 as well as its therapeutic applications. In the cardiovascularfield, this compound has proved particularly useful especially as anantiarrhythmic agent.

[0005] There has been reported in patent EP0471609, mentioned above, amethod for preparing 3-[4-(aminoalkoxy)benzoyl]benzofuran orbenzo[b]thiophene derivatives by attaching an aminoalkoxybenzoyl chainto a benzofuran or benzo[b]thiophene derivative, according to whichmethod there is first added to the benzofuran or benzo[b]thiophenederivative in question a benzoyl group containing in the para positionan oxygen protected with a methyl group, deprotection is carried out inorder to regenerate the hydroxyl functional group and finally thedesired aminoalkyl chain is introduced.

[0006] More specifically, this method when applied to the preparation ofdronedarone comprises the sequence of steps below:

[0007] a) reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride inthe presence of tin tetrachloride based on the Friedel-Crafts reactionconditions and hydrolysis to form2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,

[0008] b) demethylation of the compound thus obtained in the presence of2.25 molar equivalents of aluminum chloride and hydrolysis so as to form2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran,

[0009] c) condensation of the compound obtained withl-chloro-3-(dibutylamino)propane in the presence of potassium carbonate,to give2-butyl-3-(4-[3-(dibutylamino]propoxylbenzoyl)-5-nitrobenzofuran,

[0010] d) hydrogenation of the compound thus formed, in the presence ofplatinum oxide, which gives5-amino-2-butyl-3-(4-[3-dibutylamino)propoxy]benzoylbenzofuran,

[0011] e) reaction of the 5-aminobenzofuran derivative thus obtainedwith methanesulfonyl chloride in the presence of triethylamine, whichgives dronedarone.

[0012] However, this method is not without some disadvantages because,in particular, of the use of aluminum chloride. Indeed, the use of thismethod on an industrial scale causes high discharges of aluminumhydroxide whose treatment, in order to avoid problems of pollution, isfound to be expensive. In addition, the use of2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran should be avoided as faras possible because of its mutagenic properties.

[0013] However, the desired compound is produced with a maximum yield of60% from 2-butyl-5-nitrobenzofuran according to this method comprising arelatively large number of steps since at least five steps are necessaryfor the final formation of dronedarone.

[0014] The search for an industrial method for the preparation ofdronedarone or its pharmaceutically acceptable salts using easilyaccessible and inexpensive synthesis intermediates based on a moredirect method than the earlier method and not using aluminum chloridetherefore remains of unquestionable interest.

[0015] There has been reported in J. Med. Chem. 1984, 27, 1057-1066 amore convergent method for attaching an aminoalkoxybenzoyl chain to abenzo[b]thiophene derivative without an intermediate step ofprotecting/deprotecting the hydroxyl functional group. However, thismethod still proposes on page 1064 the use of aluminum chloride inparticularly large quantities since it is of the order of 9 molarequivalents.

[0016] According to this method, the benzo[b]thiophene derivative inquestion is condensed, in an organic phase consisting of dichloroethane,with the hydrochloride of the chloride of the aminoalkoxybenzoylderivative, this being in the presence of aluminum chloride.

[0017] After hydrolysis, the hydrochloride of the desired3-[4-(aminoalkoxy)benzoyl]benzo[b]thiophene is recovered partly from theorganic phase and partly from the aqueous phase by three extractionswith chloroform and then treated with sodium hydroxide.

[0018] In the context of the preparation of the present invention, thismethod is applied starting with 2-butyl-5-nitrobenzofuran in order todirectly prepare2-butyl-3-(4-[3-(dibutylamino)propoxyl]benzoyl)-5-nitrobenzofuran, thisbeing using the following steps:

[0019] treatment of 2-butyl-5-nitrobenzofuran by means of4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of 9 molar equivalents of aluminum chloride, this being in anorganic phase,

[0020] hydrolysis, recovery of2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuranhydrochloride and treatment with sodium hydroxide so as to form thedesired2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran.

[0021] However, this method has proved unsuitable at the industriallevel because, on the one hand, of the enormous quantity of aluminumhydroxide thus produced and, on the other hand, of the large amount ofimpurities recovered and, consequently, of the low yield of2-butyl-3-(4-[3-(dibutylamino)propoxy]-5-nitrobenzofuran (20 to 30%).

[0022] However, it has been found, surprisingly, that it is possible,starting with 2-butyl-5-(methanesulfonamido)benzofuran and usingappropriate quantities of a Lewis acid in a Friedel-Crafts reaction, todirectly obtain dronedarone hydrochloride with excellent yields sincethey are at least 85%, it being possible for this hydrochloride to berecovered in a remarkably advantageous manner since it is practicallyentirely found not in the aqueous phase as might have been predicted butin the organic phase used, which avoids the need to carry out severalextractions of this same aqueous phase as in the earlier method.

[0023] In addition, the 2-butyl-5-(methanesulfonamido)benzofuran mayitself be obtained with great ease and high yields, since they are above75%, from 5-amino-2-butylbenzofuran and even from the precursor of thelatter, namely 2-butyl-5-nitrobenzofuran.

[0024] 2-Butyl-5-(methanesulfonamido)benzofuran is a novel product whichcan be easily obtained in crystalline form, unlike2-butyl-5-nitrobenzofuran whose crystalline state may be difficult toobtain. This methanesulfonamido derivative therefore has an undeniableadvantage over the nitro derivative in question.

[0025] Consequently, the invention relates to2-butyl-5-(methanesulfonamido)benzofuran as a novel industrial productuseful in particular as synthesis intermediate, for example for thepreparation of dronedarone or its pharmaceutically acceptable salts.

[0026] Thus, according to the invention,2-butyl-5-(methanesulfonamido)benzofuran is prepared by reacting5-amino-2-butylbenzofuran with methanesulfonyl chloride ormethanesulfonic anhydride, the reaction taking place in the presence ofan acid acceptor such as triethylamine or ammonia, giving the desiredcompound. Generally, the reaction takes place at room temperature and inone or more apolar solvents preferably chosen from halogenatedhydrocarbons and ethers such as, for example, methyl tert-butyl ether,tetrahydrofuran, dichloromethane or dichloroethane.

[0027] 5-Amino-2-butylbenzofuran, for its part, may be prepared byhydrogenating 2-butyl-5-nitrobenzofuran in the presence of anappropriate catalyst, giving the desired compound.

[0028] As catalyst, a platinum derivative such as platinum oxide or anammonium formate/palladized charcoal system is normally used, thehydrogenation taking place at room temperature and optionally underpressure, for example at a pressure of the order of 20 to 30 bar.

[0029] This hydrogenation; which is carried out with excellent yields ofup 100%, has unquestionable advantages compared with the hydrogenationof 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran ofthe earlier method. Indeed, 2-butyl-5-nitrobenzofuran, apart from thenitro group, contains no other functional group which can be modified bythis reaction, unlike the2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuranderivative whose hydrogenation can prove difficult because of theby-products formed.

[0030] As indicated above, 2-butyl-5-(methanesulfonamido)benzofuran canbe used for the preparation of dronedarone.

[0031] Thus, according to the invention, dronedarone is prepared byfirst forming its hydrochloride, that is to say by reacting, in anorganic phase, 2-butyl-5-(methanesulfonamido)benzofuran with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being inthe presence of a Lewis acid as catalyst and by hydrolyzing in order toform dronedarone hydrochloride which is recovered from the organicphase.

[0032] The reaction, which is performed under Friedel-Crafts reactionconditions, is normally carried out at room temperature and in anorganic phase consisting of one or more solvents chosen from halogenatedor nonhalogenated hydrocarbons, preferably of the aliphatic, alicyclicor aromatic type. Generally, halogenated, preferably chlorinated,hydrocarbons of the aliphatic, alicyclic or aromatic type, such as forexample dichloromethane, dichloroethane or chlorobenzene, are used.

[0033] In addition, the Lewis acid may be aluminum chloride, zincchloride, boron trifluoride, stannic chloride, titanium tetrachloride orpreferably ferric chloride. It is also possible to use a mixture ofthese Lewis acids. This Lewis acid is used at concentrations which donot exceed 5 molar equivalents, in particular in an amount of 2 to 5molar equivalents. More particularly, this Lewis acid is used atconcentrations which do not exceed 4 molar equivalents. Still moreparticularly, this Lewis acid is used at concentrations which do notexceed 3 molar equivalents, in particular in an amount of 2 to 3 molarequivalents, preferably 2.5 molar equivalents.

[0034] Finally, 4-[3-(dibutylamino)propoxy]benzoyl chloridehydrochloride is used at concentrations of the order of 1 to 1.3 molarequivalents.

[0035] The dronedarone hydrochloride thus obtained is then converted,after isolation, to dronedarone by treating with a basic agent such asan alkali metal hydroxide, for example sodium hydroxide, an alkali metalcarbonate or an alkali metal hydrogen carbonate such as sodium hydrogencarbonate, which gives the desired compound.

[0036] According to a preferred embodiment of the invention, dronedaroneis prepared without isolating its hydrochloride which is transientlyformed, that is to say in the actual medium where this hydrochloride isprepared.

[0037] Consequently, according to one variant of the invention,dronedarone is prepared by means of a method according to which, in anorganic phase consisting of one or more solvents chosen from halogenatedor nonhalogenated hydrocarbons, 2-butyl-5-(methanesulfonamido)benzofuranis reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloridehydrochloride, this being in the presence of a maximum of 5 molarequivalents, in particular of a maximum of 4 molar equivalents, andpreferably of a maximum of 3 molar equivalents of a Lewis acid ascatalyst, hydrolysis is carried out in order to obtain transiently, andwithout isolation, dronedarone hydrochloride which is recovered in theorganic phase and the hydrochloride formed is treated with a basicagent, giving dronedarone.

[0038] According to another aspect of the invention, dronedarone may beobtained using a three-stage method starting with2-butyl-5-nitrobenzofuran.

[0039] Consequently, another subject of the invention relates to thepreparation of dronedarone starting with 2-butyl-5-nitrobenzofuranaccording to a method by which:

[0040] a) 2-butyl-5-nitrobenzofuran is hydrogenated in the presence ofan appropriate catalyst, to form 5-amino-2-butylbenzofuran,

[0041] b) the compound thus obtained is reacted with methanesulfonylchloride or methanesulfonic anhydride, the reaction taking place in thepresence of an acid acceptor, to form2-butyl-5-(methanesulfonamido)benzofuran,

[0042] c) the methanesulfonamido derivative thus obtained is reacted, inan organic phase consisting of one or more solvents chosen fromhalogenated or nonhalogenated hydrocarbons, with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being inthe presence of a maximum of 5 molar equivalents, in particular of amaximum of 4 molar equivalents and preferably of a maximum of 3 molarequivalents of a Lewis acid as catalyst, hydrolysis is carried out inorder to obtain transiently, and without isolation, dronedaronehydrochloride which is recovered in the organic phase and thehydrochloride formed is treated with a basic agent, giving dronedarone.

[0043] Subsequently, the dronedarone obtained according to either methodor variant of the invention may be treated, if necessary, with anorganic or inorganic acid to form a pharmaceutically acceptable salt ofthis compound.

[0044] 4-[3-(Dibutylamino)propoxy]benzoyl chloride hydrochloride, forits part, may be prepared according to the succession of steps below:

[0045] a) 1-dibutylamino-3-chloropropane is reacted with a C₁-C₄ alkylp-hydroxybenzoate, for example methyl p-hydroxybenzoate, this being inthe presence of a basic agent such as an alkali metal carbonate, forexample potassium carbonate, to give a methyl4-[3-(dibutylamino)propoxy]benozate,

[0046] b) the ester thus obtained is saponified in the presence of analkali metal hydroxide, for example sodium hydroxide, and then the saltthus formed is treated with hydrochloric acid to give4-[3-(dibutylamino)propoxy]benzoic acid hydrochloride,

[0047] c) the hydrochloride thus formed is treated with a chlorinatingagent, for example thionyl chloride, to give the desired compound.

[0048] This use of the method of the invention for the preparation ofdronedarone has proved superior to the method of patent EP0471609 inparticular because of a smaller number of steps, namely three instead offive starting with 2-butyl-5-nitrobenzofuran and a higher overall yieldsince it is greater than 65%, or even 70%.

[0049] Moreover, this method of the invention involves, in each step,benzofuran intermediates of relatively simple structure, andconsequently inexpensive, unlike the earlier method which uses in eachof its steps benzofuran derivatives of a fairly elaborate structure.

[0050] The following nonlimiting examples illustrate the invention.

PREPARATIONS

[0051] A. 1-Dibutylamino-3-chloropropane

[0052] Into a 1 l reactor, there are introduced 288.4 g (3.392 mol) of20% aqueous ammonia, and then there are added, over 10 minutes and atroom temperature (22±2° C.), 618 g (1.696 mol) of1-dibutylamino-3-chloropropane hydrochloride (titer 66.5%). The mediumis stirred for 45 minutes at room temperature and it is allowed toseparate by settling for 30 minutes. The bottom aqueous phase (pH =11)is removed, and the organic phase is washed with 300 ml of deionizedwater at room temperature. The medium is stirred for 30 minutes,separated by settling for 30 minutes and the bottom aqueous phase (pH=9) is drawn off.

[0053] In this manner, 346.3 g of the desired compound are recovered.

[0054] Yield: 99.4%.

[0055] B. Methyl 4-[3-(dibutylamino)propoxy]-benzoate

[0056] 200 g (1.3 mol) of methyl p-hydroxybenzoate and 1.6 l ofN,N-dimethylformamide are introduced into a 2 l round-bottomed flask.The mixture is stirred and 232 g (1.66 mol) of potassium carbonate areadded thereto. The medium is heated to 100° C. and then the1-dibutylamino-3-chloropropane prepared in step A. above is introducedover 10 minutes. The reaction medium is kept for 1 hour at 100 ±2° C.and then cooled to 25° C. The inorganic salts are filtered off and thefiltrate is rinsed with twice 50 ml of N,N-dimethylformamide andconcentrated in a rotary evaporator until a temperature of 85° C. and apressure of 5 mmHg are obtained.

[0057] In this manner, 472.7 g of the desired product are obtained inthe form of an orange oil.

[0058] Purity (HPLC or high-performance liquid chromatography)

[0059] Desired compound: 99.7%

[0060] Methyl p-hydroxybenzoate: 0.1%

[0061] C. 4-[3-(Dibutylamino)propoxy]benzoic acid hydrochloride

[0062] 436.3 g of methyl 4-[3-(dibutylamino)-propoxy]benzoate and 1.092l of methanol are introduced into a 2 l round-bottomed flask. Themixture is stirred and 360 g (1.8 mol) of 20% sodium hydroxide areintroduced over about 5 minutes.

[0063] The medium is heated at 65° C. for about 30 minutes and kept atthis temperature for 2 hours. The reaction medium is cooled to 30° C.and concentrated in a rotary evaporator (temperature of the bath: 30°C., pressure 30 mmHg), which gives 937 g of residue which is diluted byadding 2.8 l of deionized water. The solution is cooled to 10±2° C. andthen, without exceeding 20° C., 260 ml (about 3 mol) of a 36%hydrochloric acid are introduced.

[0064] It is checked that the pH is less than 1, and then the suspensionis cooled to 10±2° C. This temperature is maintained for 30 minutes, thecrystals formed are drained and the cake is washed with twice 200 ml ofdeionized water. It is then dried in a ventilated oven at 50° C. to aconstant weight (24 hours).

[0065] In this manner, 416.2 g of the desired compound are obtained.

[0066] Yield: 100%.

[0067] Purity (HPLC)

[0068] Desired compound: 99.5%

[0069] Methyl 4-[3-(dibutylamino)propoxy]benzoate:

[0070] 0.1%

[0071] D. 4-[3-(Dibutylamino)propoxy]benzoyl chloride hydrochloride

[0072] 63.3 g (0.184 mol) of 4-[3-(dibutylamino)propoxy]benzoic acidhydrochloride, 300 ml of chlorobenzene and 2 drops ofN,N-dimethylformamide are introduced into a round-bottomed flask. 43.8 g(0.368 mol) of thionyl chloride are introduced, over about 45 minutes,while the mixture is kept under an inert atmosphere. The medium is keptfor 1 hour at 85±1° C. and then about 115 g of a mixture ofchlorobenzene and thionyl chloride is distilled under a gradual vacuum.

[0073] In this manner, the desired compound is obtained in the form ofan oil and in crude form.

EXAMPLE 1

[0074]5-Amino-2-butylbenzofuran

[0075] Method I

[0076] 182 g.of 2-butyl-5-nitrobenzofuran and 730 ml of ethanol areintroduced into a hydrogenation apparatus, and then 9.1 g of about 97%platinum oxide are added. A hydrogen stream is bubbled through, withstirring at a pressure of 25 bar (the temperature increasesspontaneously to 60° C.) and the medium is cooled to 20° C. The mediumis filtered, rinsed with 400 ml of ethanol and concentrated at 50° C.under vacuum.

[0077] In this manner, 5-amino-2-butylbenzofuran is obtained.

[0078] Weight yield: 99.2%

[0079] Method II

[0080] 1 g of 2-butyl-5-nitrobenzofuran and 4 ml of ethanol areintroduced into a closed reactor and then 1.48 g of ammonium formate and0.1 g of 5% palladized charcoal are added. The medium is stirred andheated at 50° C. for 5 hours and then cooled to 20° C., and filtered.The medium is rinsed with 4 ml of ethanol and concentrated at 50° C.,under vacuum.

[0081] In this manner, 5-amino-2-butylbenzofuran is obtained.

EXAMPLE 2

[0082]2-Butyl-5-(methan sulfonamido)benzofuran

[0083] 100 g of 5-amino-2-butylbenzofuran, 192 ml of tetrahydrofuran and96 ml of methyl tert-butyl ether are introduced into a round-bottomedflask. 59.35 g of methanesulfonyl chloride are added, at 200° C.,followed by 43.23 g of 20% aqueous ammonia. 44.51 g of methanesulfonylchloride are then introduced, followed by 86.47 g of 20% aqueousammonia. 48 ml of water are then added, the medium is separated bysettling and the organic phase is washed twice with 211 g of 10% aqueoussodium chloride solution. The medium is separated by settling andconcentrated at 400° C. under vacuum, to give the desired compound incrude form (weight yield: 100%).

[0084] 135.6 g of the residue thus obtained are introduced into 1220 mlof methyl tert-butyl ether and 13.56 g of carbon black are added.

[0085] The medium is stirred under reflux for 15 minutes, filtered andrinsed with 204 ml of methyl tert-butyl ether. The filtrate is heatedunder reflux and then cooled to 400° C. The medium is then seeded with2-butyl-3-(methanesulfonamido)benzofuran, cooled to −5° C. and stirredat this temperature for 30 minutes.

[0086] The medium is filtered and rinsed at −50° C. with twice 1 volumeof methyl tert-butyl ether.

[0087] In this manner, the desired compound is obtained with a weightyield of 78.5%.

[0088] NMR (nuclear magnetic resonance) spectrum (300 MHz)

[0089] Solvent: CDC1₃

[0090] Concentration: 40 mg/ml

[0091] Temperature for analysis: 300 K

Chemical Coupling shifts δ ± Integra- constant Attri- 0.01 ppmMultiplicity tion |J| ± 0.5 Hz bution 7.42 doublet 1 ⁴J_(H—H) ≈ 2.0 H(4)7.36 doublet 1 ³J_(H—H) ≈ 8.5 H(7) 7.08 doublet of 1 ³J_(H—H) ≈ 8.5 H(6)doublets ⁴J_(H—H) ≈ 2.0 6.83-6.89 broad signals 1 — NH 6.35 singlet 1 —H(3) 2.97 singlet 3 — CH₃SO₂ 2.76 triplet 2 ³J_(H—H) ≈ 7.5 CH₂(10) 1.72quintuplet 2 ³J_(H—H) ≈ 7.5 CH₂(11) 1.42 sextuplet 2 ³J_(H—H) ≈ 7.5CH₂(12) 0.95 triplet 3 ³J_(H—H) ≈ 7.5 CH₃(13)

EXAMPLE 3

[0092] Dronedarone hydrochloride

[0093] A mixture of 8 g of 2-butyl-5-(methanesulfonamido)benzofuran,11.9 g of 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride and24 ml of dichloromethane is first of all prepared. This mixture is thenintroduced into a medium consisting of 11.9 g of ferric chloride and 24ml of dichloromethane. The reaction medium is heated under reflux for 2hours and cooled to 20° C. 40 ml of water are added and the medium isseparated by settling.

[0094] In this manner, dronedarone hydrochloride is obtained in crudeform.

[0095] Chemical yield: 90%.

EXAMPLE 4

[0096] Dronedarone hydrochloride

[0097] A. Dronedarone

[0098] The dronedarone hydrochloride obtained in Example 3 above iswashed twice, this being with 24 ml of water, and then with 16 ml of a10% aqueous sodium hydroxide solution and finally with 16 ml of water.

[0099] In this manner, dronedarone in crude form is obtained.

[0100] Chemical yield: 86%.

[0101] B. Dronedarone hydrochloride

[0102] The dronedarone in crude form obtained in the preceding paragraphA. is concentrated and taken up in 24 ml of isopropanol. 3.24 g of 37%hydrochloric acid are added and then the medium is cooled to 0° C. Themedium is filtered and washed with 8 ml of isopropanol.

[0103] In this manner, dronedarone hydrochloride is obtained.

EXAMPLE 5

[0104] Dronedarone hydrochloride—Preparation on a pilot scale

[0105] 5.1. Dronedarone hydrochloride

[0106] A mixture of 10 kg of 2-butyl-5-(methanesulfonamido)benzofuran,13 kg of 4-[3-(dibutylamino)propoxy]benzoyl hydrochloride and 70 1 ofdichloromethane is first of all prepared. 19.9 kg of aluminum chlorideare then introduced into this mixture (4 molar equivalents of Lewis acidare thus used; 2.5 molar equivalents of ferric chloride were used forthe above Example 3). The medium is stirred at 25° C. for two hours.This medium is added to 60 l of water and the medium is separated bysettling.

[0107] In this manner, dronedarone hydrochloride in crude form isobtained.

[0108] Chemical yield =90%.

[0109] 5.2. Dronedarone and then dronedarone hydrochloride

[0110] The dronedarone hydrochloride obtained in the preceding step iswashed 5 times with 60 l of water. The dronedarone is concentrated andtaken up in 94 l of isopropanol. 1.8 kg of water and 0.38 kg ofhydrochloric acid are added. The medium is cooled to −5° C. The mediumis filtered, and washed with 22 l of isopropanol.

[0111] In this manner, dronedarone hydrochloride is obtained.

[0112] Chemical yield =90%.

1. 2-Butyl-5-(methanesulfonamido)benzo-furan.
 2. A method for preparing2-butyl-5-(methanesulfonamido)benzofuran, wherein5-amino-2-butylbenzofuran is reacted with methanesulfonyl chloride ormethansulfonic anhydride, the reaction taking place in the presence ofan acid acceptor, giving the desired compound.
 3. A method for preparingdronedarone, wherein, in an organic phase consisting of one or moresolvents chosen from halogenated or nonhalogenated hydrocarbons,2-butyl-5-(methanesulfonamido)benzofuran is reacted with4-[3-(dibutylamino)propoxy]benzoyl, chloride hydrochloride, this beingin the presence of a maximum of 5 molar equivalents of a Lewis acid ascatalyst, and then hydrolysis is carried out so as to form dronedaronehydrochloride which is recovered in the organic phase, which is isolatedand which is treated with a basic agent, to give the desired compound.4. The method as claimed in claim 3, wherein2-butyl-5-(methanesulfonamido)benzofuran is reacted with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 4 molar equivalents of the Lewis acid.
 5. Themethod as claimed in claim 3 or 4, wherein2-butyl-5-(methanesulfonamido)benzofuran is reacted with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 3 molar equivalents of the Lewis acid.
 6. Amethod for preparing dronedarone, wherein, in an organic phaseconsisting of one or more solvents chosen from halogenated ornonhalogenated hydrocarbons, 2-butyl-5-(methanesulfonamido)benzofuran isreacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride,this being in the presence of a maximum of 5 molar equivalents of aLewis acid as catalyst, and then hydrolysis is carried out in order toobtain transiently, and without isolation, dronedarone hydrochloridewhich is recovered in the organic phase and which is treated with abasic agent, giving the desired compound.
 7. The method as claimed inclaim 6, wherein 2-butyl-5-(methanesulfonamido)benzofuran is reactedwith 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 4 molar equivalents of the Lewis acid.
 8. Themethod as claimed in claim 6 or 7, wherein2-butyl-5-(methanesulfonamido)benzofuran is reacted with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 3 molar equivalents of the Lewis acid.
 9. Amethod for preparing dronedarone, wherein: a) 2-butyl-5-nitrobenzofuranis hydrogenated in the presence of an appropriate catalyst, to form5-amino-2-butylbenzofuran, b) the compound thus obtained is reacted withmethanesulfonyl chloride or methanesulfonic anhydride, the reactiontaking place in the presence of an acid acceptor, to form2-butyl-5-(methanesulfonamido)benzofuran, c) the methanesulfonamidoderivative thus obtained is reacted, in an organic phase consisting ofone or more solvents chosen from halogenated or nonhalogenatedhydrocarbons, with 4-[3-(dibutylamino)propoxy]benzoyl chloridehydrochloride, this being in the presence of a maximum of 5 molarequivalents of a Lewis acid as catalyst, and then hydrolysis is carriedout in order to obtain transiently, and without isolation, dronedaronehydrochloride which is recovered in the organic phase and which istreated with a basic agent, giving the desired compound.
 10. The methodas claimed in claim 9, wherein in step c), the methanesulfonamidoderivative thus obtained is reacted with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 4 molar equivalents of the Lewis acid.
 11. Themethod as claimed in claim 9 or 10, wherein in step c), themethanesulfonamido derivative thus obtained is reacted with4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in thepresence of a maximum of 3 molar equivalents of the Lewis acid.
 12. Themethod as claimed in one of claims 3 to 11, wherein the organic phaseconsists of one or more solvents chosen from halogenated hydrocarbons ofthe aliphatic, alicyclic or aromatic type.
 13. The method as claimed inone of claims 3 to 12, wherein the Lewis acid is chosen from the groupconsisting of aluminum chloride, zinc chloride, boron trifluoride,stannic chloride, titanium tetrachloride, ferric chloride and mixturesthereof.
 14. The method as claimed in one of claims 3 to 13, wherein theLewis acid is ferric chloride.
 15. The method as claimed in one ofclaims 3, 6, 9, 13 and 14, wherein the Lewis acid is used in an amountof 2 to 5 molar equivalents.
 16. The method as claimed in one of claims3 to 11, 13 and 14, wherein the Lewis acid is used in an amount of 2 to3 molar equivalents.
 17. The method as claimed in one of claims 3 to 16,wherein the 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride isused at concentrations of the order of 1 to 1.3 molar equivalents. 18.The method as claimed in one of claims 3 to 17, characterized in thatthe basic agent is sodium hydroxide or sodium hydrogen carbonate.